The long-term goal of our research is to determine the effects of visceral fat on insulin sensitivity and longevity. Improvements in healthcare during the last century have significantly increased the average lifespan in developed countries. With the growing population of elderly, physicians are treating a greater number of patients suffering from age-related diseases. Growing incidence of metabolic syndrome, atherosclerotic disease, insulin resistance and diabetes mellitus-which jumps from 7% to almost 20% of the population after age 75-challenges the global medical community. Two well-documented factors affecting insulin resistance and diabetes are a lack of physical activity and an unhealthy diet, which may cause obesity when combined. Several studies with mice and rats indicated that obesity causes insulin resistance and has negative effects on longevity. Calorie restriction decreases the volume of fat, improves insulin sensitivity and extends longevity. One could infer that a lean body promotes healthy insulin action and a longer life. However, Ames dwarf and GHRKO mice are both hyper-sensitive to injected insulin and long-lived despite an increased or normal volume of fat (depending on age). What regulates high insulin sensitivity and longer lifespan in these mutant animals? We hypothesize that Prop1df mutation and GHR knockout cause beneficial alterations in white adipose tissue that influences insulin sensitivity and longevity. In the proposed studies, we will investigate effects of a high fat diet (HFD) and visceral fat depots on insulin signaling and longevity in normal, Ames dwarf and GHRKO mice. We propose that long-living Ames dwarf and GHRKO mice will be resistant to the detrimental effects of HFD. Also based on our preliminary data indicating a very different, nearly opposite role of visceral fat in the regulation of insulin signaling in GHRKO and Ames dwarf mice in comparison to normal animals, we propose that visceral fat removal will not improve insulin action and longevity of these long-lived mutants. We believe that these studies will elucidate the interaction of visceral fat depots and diet on insulin signaling and longevity. The following specific aims are proposed: Aim 1: Analyze the interactive effects of surgical removal of visceral fat depots and genotype on insulin signaling, adipocytokines, lipid metabolism and longevity in GHRKO, Ames dwarf and normal mice. Aim 2: Analyze the effects of a high fat diet (HFD) on insulin signaling, adipocytokines, cytokines, lipid and metabolism in GHRKO, Ames dwarf and normal mice. Aim 3: Determine the function of visceral fat developed in the absence of GH action on insulin signaling in vivo by transplanting visceral fat from GHRKO into normal mice. PUBLIC HEALTH RELEVANCE: Identifying the mechanisms and/or causes of extended longevity and delayed aging is one of the great scientific challenges of the 21st century. Do these mechanisms involve genetics, lifestyle or dietary choices? If one could identify the mechanisms involved, future research would have targets to extend lifespan and improve the "healthspan" of the human race.